Non-Hodgkin lymphoma (NHL) is the 7th most frequent cancer (Siegel et al., 2012). Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL accounting for ˜25% of all lymphoma cases (Swerdlow, 2008). Gene expression profiling allowed subclassification of DLBCL into distinct molecular subtypes including: germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL and primary mediastinal B-cell lymphoma (PMBL) (Alizadeh et al., 2000; Rosenwald et al., 2003). These subtypes differ significantly in their spectrum of recurrent somatic mutations, dependence on different signaling pathways and response to current standard therapies (Lenz et al., 2008b; Wright et al., 2003). Patients with the GCB subtype have a significantly better overall survival compared to those with the ABC subtype (Alizadeh et al., 2000; Rosenwald et al., 2002). Improved therapies are needed for all DLBCLs but most urgently for ABC-DLBCLs, which are the most chemo-resistant.
ABC-DLBCL is characterized by its reliance on the oncogenic activation of the NF-κB pathway through several different mechanisms. These mostly involve somatic mutations in molecules participating in signaling downstream of the B-cell receptor (BCR) including: activating mutations of CARMA1/CARD11 (Lenz et al., 2008a) and CD79A/B (Davis et al., 2010), homozygous deletion/inactivating mutations of TNFAIP3/A20 (Compagno et al., 2009; Honma et al., 2009) or activating mutations of MYD88 downstream of the Toll-like receptor (Ngo et al., 2011). CARMA1 forms part of the CBM complex (CARMA1-BCL10-MALT1) and mediates NF-κB activation downstream of the B-cell receptor, T-cell receptor (Ruefli-Brasse et al., 2003; Ruland et al., 2003) and ITAM-coupled NK cell receptors (Gross et al., 2008). The MALT1 subunit is the active signaling component of the CBM complex (Lucas et al., 2001) and features protease activity that cleaves and inactivates inhibitors of the NF-κB signaling pathway such as TNFAIP3/A20 (Coornaert et al., 2008), CYLD (Staal et al., 2011) and RELB (Hailfinger et al., 2011) or the BCL10 protein (Rebeaud et al., 2008), indirectly activating NF-κB signaling. MALT1 translocations (t(11; 18)(q21; q21) which produces an API2-MALT1 fusion and the t(14; 18)(q32; q21) that results in the IGH-MALT1 translocation) are detected in up to 55% of patients with MALT-type lymphomas (Farinha and Gascoyne, 2005). This translocations lead to overexpression of MALT1 and, in the case of the API2-MALT1 translocation, constitutive activation of the pathway (Dierlamm et al., 1999; Sanchez-Izquierdo et al., 2003; Streubel et al., 2003). Constitutive expression of MALT1 in mice induces a disease that is similar to MALT lymphomas in humans, and induces ABC-like DLBCLs in a p53 null background (Vicente-Duenas et al., 2012). MALT1 has not been found mutated or translocated in DLBCL, but is gained along with BCL2 and this low copy number amplification is associated with an ABC-DLBCL phenotype (Dierlamm et al., 2008). Moreover, ABC-DLBCL cell lines have been shown to be dependent on the MALT1 catalytic activity (Ferch et al., 2009; Hailfinger et al., 2009; Ngo et al., 2006).
MALT1 is a paracaspase, related to the caspase (cysteine-aspartic proteases) family of proteases but which cleaves after arginine or lysine residues instead of aspartate (Rebeaud et al., 2008). MALT1 null animals display defects in B and T cell function but are otherwise healthy (Ruefli-Brasse et al., 2003; Ruland et al., 2003), and MALT1 is the only paracaspase in the human genome. These factors suggest that MALT1 targeted therapy would likely be well tolerated with little or manageable toxicity. Consequently, MALT1 represents a potentially important therapeutic target for ABC-DLBCL and MALT lymphoma.